Acid ceramidase regulates innate immune memory

Nils Rother; Cansu Yanginlar; Geoffrey Prévot; Inge Jonkman; Maaike Jacobs; Mandy M.T. van Leent; Julia van Heck; Vasiliki Matzaraki; Anthony Azzun; Judit Morla-Folch; Anna Ranzenigo; William Wang; Roy van der Meel; Zahi A. Fayad; Niels P. Riksen; Luuk B. Hilbrands; Rik G.H. Lindeboom; Joost H.A. Martens; Michiel Vermeulen; Leo A.B. Joosten; Mihai G. Netea; Willem J.M. Mulder; Johan van der Vlag; Abraham J.P. Teunissen; Raphaël Duivenvoorden

doi:10.1016/j.celrep.2023.113458

Acid ceramidase regulates innate immune memory

Nils Rother, Cansu Yanginlar, Geoffrey Prévot, Inge Jonkman, Maaike Jacobs, Mandy M.T. van Leent, Julia van Heck, Vasiliki Matzaraki, Anthony Azzun, Judit Morla-Folch, Anna Ranzenigo, William Wang, Roy van der Meel, Zahi A. Fayad, Niels P. Riksen, Luuk B. Hilbrands, Rik G.H. Lindeboom, Joost H.A. Martens, Michiel Vermeulen, Leo A.B. JoostenMihai G. Netea, Willem J.M. Mulder, Johan van der Vlag, Abraham J.P. Teunissen, Raphaël Duivenvoorden (Corresponding author)

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Abstract

Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

Original language	English
Article number	113458
Number of pages	25
Journal	Cell Reports
Volume	42
Issue number	12
DOIs	https://doi.org/10.1016/j.celrep.2023.113458
Publication status	Published - 26 Dec 2023

Funding

This work was supported by the Hypatia grant by the Radboud university medical center and the Senior Kolff grant by the Dutch Kidney Foundation (to R.D.). C.Y. is supported by the Radboud university medical center PhD fellow program. M.G.N. L.A.B.J. and N.P.R. are supported by the Dutch Heart Foundation IN-CONTROL CVON grant (CVON2018-27). M.G.N. was supported by an ERC Advanced Grant (no. 833247) and a Spinoza Grant of the Netherlands Organization for Scientific Research. N.R. and R.D. designed the study. N.R. C.Y. G.P. I.J. M.J. M.M.T.v.L. J.v.H. V.M. A.A. R.v.d.M. Z.A.F. N.P.R. L.B.H. L.A.B.J. W.J.M.M. M.G.N. J.v.d.V. A.J.P.T. and R.D. designed, performed, and oversaw the experiments. G.P. A.A. W.J.M.M. and A.J.P.T. developed sphingolipid-loaded nanobiologics. N.R. C.Y. I.J. M.J. and R.D. performed in vitro trained immunity experiments. N.R. and J.H. performed Seahorse metabolic experiments. N.R. C.Y. and R.D. collected and prepared samples for lipidomic, transcriptomic, and epigenetic analysis. R.G.H.L. J.H.A.M. and M.V. performed RNA-seq and ChIP-seq data analysis. V.M. performed FTI-QTL analysis. The manuscript was written by N.R. and R.D. All authors contributed to writing the manuscript and approved the final draft. R.D. provided funding. The authors declare no competing interests. This work was supported by the Hypatia grant by the Radboud university medical center and the Senior Kolff grant by the Dutch Kidney Foundation (to R.D.). C.Y. is supported by the Radboud university medical center PhD fellow program. M.G.N., L.A.B.J., and N.P.R. are supported by the Dutch Heart Foundation IN-CONTROL CVON grant ( CVON2018-27 ). M.G.N. was supported by an ERC Advanced Grant (no. 833247 ) and a Spinoza Grant of the Netherlands Organization for Scientific Research .

Funders	Funder number
H2020 European Research Council	833247
Hartstichting, Nederlandse	CVON2018-27
Nierstichting Nederland
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Radboud University Medical Center

Keywords

acid ceramidase
CP: Immunology
epigenetics
immune memory
innate immunity
lipid metabolism
monocytes
nanobiologics
sphingolipids
trained immunity

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Rother, N., Yanginlar, C., Prévot, G., Jonkman, I., Jacobs, M., van Leent, M. M. T., van Heck, J., Matzaraki, V., Azzun, A., Morla-Folch, J., Ranzenigo, A., Wang, W., van der Meel, R., Fayad, Z. A., Riksen, N. P., Hilbrands, L. B., Lindeboom, R. G. H., Martens, J. H. A., Vermeulen, M., ... Duivenvoorden, R. (2023). Acid ceramidase regulates innate immune memory. Cell Reports, 42(12), Article 113458. https://doi.org/10.1016/j.celrep.2023.113458

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title = "Acid ceramidase regulates innate immune memory",

abstract = "Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.",

keywords = "acid ceramidase, CP: Immunology, epigenetics, immune memory, innate immunity, lipid metabolism, monocytes, nanobiologics, sphingolipids, trained immunity",

author = "Nils Rother and Cansu Yanginlar and Geoffrey Pr{\'e}vot and Inge Jonkman and Maaike Jacobs and {van Leent}, {Mandy M.T.} and {van Heck}, Julia and Vasiliki Matzaraki and Anthony Azzun and Judit Morla-Folch and Anna Ranzenigo and William Wang and {van der Meel}, Roy and Fayad, {Zahi A.} and Riksen, {Niels P.} and Hilbrands, {Luuk B.} and Lindeboom, {Rik G.H.} and Martens, {Joost H.A.} and Michiel Vermeulen and Joosten, {Leo A.B.} and Netea, {Mihai G.} and Mulder, {Willem J.M.} and {van der Vlag}, Johan and Teunissen, {Abraham J.P.} and Rapha{\"e}l Duivenvoorden",

year = "2023",

month = dec,

day = "26",

doi = "10.1016/j.celrep.2023.113458",

language = "English",

volume = "42",

journal = "Cell Reports",

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Rother, N, Yanginlar, C, Prévot, G, Jonkman, I, Jacobs, M, van Leent, MMT, van Heck, J, Matzaraki, V, Azzun, A, Morla-Folch, J, Ranzenigo, A, Wang, W, van der Meel, R, Fayad, ZA, Riksen, NP, Hilbrands, LB, Lindeboom, RGH, Martens, JHA, Vermeulen, M, Joosten, LAB, Netea, MG , Mulder, WJM, van der Vlag, J, Teunissen, AJP & Duivenvoorden, R 2023, 'Acid ceramidase regulates innate immune memory', Cell Reports, vol. 42, no. 12, 113458. https://doi.org/10.1016/j.celrep.2023.113458

TY - JOUR

T1 - Acid ceramidase regulates innate immune memory

AU - Rother, Nils

AU - Yanginlar, Cansu

AU - Prévot, Geoffrey

AU - Jonkman, Inge

AU - Jacobs, Maaike

AU - van Leent, Mandy M.T.

AU - van Heck, Julia

AU - Matzaraki, Vasiliki

AU - Azzun, Anthony

AU - Morla-Folch, Judit

AU - Ranzenigo, Anna

AU - Wang, William

AU - van der Meel, Roy

AU - Fayad, Zahi A.

AU - Riksen, Niels P.

AU - Hilbrands, Luuk B.

AU - Lindeboom, Rik G.H.

AU - Martens, Joost H.A.

AU - Vermeulen, Michiel

AU - Joosten, Leo A.B.

AU - Netea, Mihai G.

AU - Mulder, Willem J.M.

AU - van der Vlag, Johan

AU - Teunissen, Abraham J.P.

AU - Duivenvoorden, Raphaël

PY - 2023/12/26

Y1 - 2023/12/26

N2 - Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

AB - Innate immune memory, also called “trained immunity,” is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

KW - acid ceramidase

KW - CP: Immunology

KW - epigenetics

KW - immune memory

KW - innate immunity

KW - lipid metabolism

KW - monocytes

KW - nanobiologics

KW - sphingolipids

KW - trained immunity

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U2 - 10.1016/j.celrep.2023.113458

DO - 10.1016/j.celrep.2023.113458

M3 - Article

C2 - 37995184

AN - SCOPUS:85177757770

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 12

M1 - 113458

ER -

Acid ceramidase regulates innate immune memory

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